3-aldehydo and 3-hydroxy-methyl-androstanes and process for same



United States Patent 3,035,068 3-ALDEHYDO AND S-HYDROXY-METHYL-AN-DROSTANES AND PROCESS FOR SAME Albert Bowers and John Edwards, MexicoCity, Mexico,

assignors to Syntex S.A., Mexico City, Mexico, a corporation of MexicoNo Drawing. Filed May 31, 1961, Ser. No. 113,643

21 Claims. (Cl. 260-397.4)

The present invention relates to novel cyclopenta nophenanthrenecompounds and to a process for the production thereof.

More particularly the present invention relates to novel 3-a1dehydroand3-hydroxymethyl-androstane derivatives.

The novel compounds of the present invention are represented by thefollowing fomulas:

In the above formulas R may be formyl (CHO) or the group -CH,-OR whereinR represents hydrogen or a hydrocarbon carboxylic acyl group containingup to 12 carbon atoms; in formula C, R may be in the 3a or 3,8-position;R represents hydrogen or a hydrocarbon carboxylic acyl group containingup to 12 carbon atoms; R3 represents hydrogen or an alkyl, alkenyl oralkinyl group containing up to 8 carbon atoms.

The acyl group is derived from hydrocarbon carboxylic acids containingless than l2 carbon atoms which may be saturated or unsaturated, ofstraight, branched, cyclic or cyclic-aliphatic chain, aromatic and maybe substituted by functional groups such as hydroxy, alkoxy containingup to carbon atoms, acyloxy containing up to 12 carbon atoms, nitro,amino or halogen. Typical ester groups are the acetate, propionate,enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate,cyclopentylpropionate, aminoacetate and B-chloropropionate. Y

3,035,068 Patented May 15, 1962 in the above formula R and R have thesame meaning as heretofore set forth.

In practicing the ,process outlined above, the starting compound whichis a dihydroallotestosterone derivative (1) is treated with triphenyl(methoxymethyDphosphonium chloride in an inert solvent such as ether andin the presence of an alkyl or aryl lithium compound, prefera'bly phenyllithium, affording the corresponding 3- methoxymethylene-androstan-17,801 derivative (H). This compound is hydrolyzed with an acid, preferablyperchloric acid, thus giving a mixture of the corresponding 3e-aldehydo(III) and 3fi-aldehydo (IV) derivatives which are separated into the twocomponents by silica gel chromatography. Reduction of these aldehydocompounds With a double metal hydride, preferably lithium aluminumhydride,- afl'ords the corresponding Zia-hydroxymethyl (IV) orBB-hydroxymethyl (V) derivatives.

The novel A -androstene derivatives of the present invention areprepared by the process illustrated by the following equation:

OR OR L-HRZ |---Rg i3 5 i i o= H-O VI I VII I I HOHzC OHC IX 3 VIII Inthe above formulas, R and R have the same meaning as previously defined.20

In practicing the process outlined above the starting testosteronederivative (VI) is treated with triphenyl (methoxyrnethyl) phosphoniumchloride in an inert solvent and in the presence of an alkyl or aryllithium compound, preferably phenyl lithium, giving the corresponding3-methoxymethylene-A androsten-175-01 derivative (VII). This compoundupon hydrolysis with an acid, such as perchloric acid, afiords thecorresponding 3- aldehydo-A -androsten-175-01 derivative (VIII) whichupon reduction, preferably with lithium aluminum hydride furnishes therespective 3-hydroxymethyl-A -androsten-17/3-ol derivative (IX).

The novel A -androstene derivatives of the present in- V'ention areprepared by the process illustrated by the following equation: 40

on on i i i 0 EC:

= I X XI OCH: '50

con;

mt U

OH i--- R2 In the above formulas, R has the same meaning as hereinbeforeset forth.

In practicing the process above outlined the starting compound A-androsten-l7fi-ol-3-one (X), [Butenandt and Dannenberg, Ber. 73, 206(1940)], is treated with triphenyl (methoxymethyl) phosphonium chloridein an inert solvent and in the presence of an alkyl or aryl lithiumcompound, preferably phenyl lithium, giving 3- methoxymethylene-A-androsten--01 (XI). Hydrolysis of this compound affords thecorresponding 3-aldehydo derivative (XII) which upon reduction furnishes3- hydroxymethyl-A -androsten-l7;3 ol (XIII).

Upon oxidation of 3-methoxymethylene-A -androsten- 175-01 (X1) in analkaline medium, such as pyridine in order not to hydrolyze theenol-ether group and using as an oxidizing agent preferably chromiumtn'oxide, there is formed the corresponding l7-keto compound (XIV). Thissteroid, by treatment with a Grignard reagent, such as methyl, vinyl, orethynyl magnesium bromide, aifords the corresponding 17u-alkyl, alkenylor alkynyl-l7fi-ol derivative (XV). Upon hydrolysis of the3-methoxymethylene group of this latter compound, there is obtained thecorresponding 3-aldehyde-A -androsten-17,8-01 derivative (XVI) whichupon reduction forms the 3-hydroxymethyl derivative (XVII).

The heretofore obtained compounds having a primary hydroxyl, such as theone present in the hydroxymethyl group, or a secondary hydroxyl, such asthe one present in the 17B-alcohols with a hydrogen at the17OL-POSltlOII, are conventionally acylated in pyridine, with anacylating agent, as for example, acetic anhydride or propionic anhydrideto give the corresponding monoor diester.

The compounds of the present inventionwith a tertiary hydroxyl, such asthe l7fi-h'ydroxyl of the Not-substituted compounds, are conventionallyacy'l'ate'd with excess acylating agent, in the presence ofp-toluen'esulfoiiic acid, to give the corresponding 17fi-ac'yloxycompounds.

The following specific examples serve 'to illustrate but are notintended to limit the scope 'of the present in vention:

HO-OH i I Example I 2. 2 .g. 'of triphenyl (methoxymethyl) .phosphoniumchloride were suspended in 50 cc. of anhydrous ether.

' 38- aldehydo 17a vinyl andro overnight. The ether was removed bydistillation; during this process, 150 cc. of tetrahydrofuran was added.When all the ether had distilled, the mixture was refluxed for 6 hoursand then part of the solvent removed under vacuum. The concentratedsolution was poured into water and the product extracted with methylenechloride. The extract was washed with water, dried over anhydrous sodiumsulfate and evaporated to dryness. Crystallization of the residue fromacetone-hexane afforded 3- methoxymethylene-androsten-l7fi-ol.

When applying the method described above to 170:-methyl-dihydroallotesterone, l7a-vinyl-dihydroallotestosterone andl7ix-ethynyl-dihydroallotestosterone, there were respectively obtained3-methoxymethylene-l7amethyl-androsten-UB-ol,3-methoxymethylene-17a-vinylandrosten-17fi-ol and3-methoxymethylene-l7a-ethynylandrosten-17fl-ol.

Example II A solution of l g. of 3-methoxymethylene-androsten- 17,B-olin 50 cc. of ether was treated with 50 cc. of ether saturated withperchloric acid for 30 minutes. The solution was then washed withaqueous sodium bicarbonate solution and water, dried over sodium sulfateand evaporated to dryness. The mixture of Zia-aldehyde and Sfl-aldehydethus obtained was separated by chromatography on silica gel. The twocompounds were separately recrystallized from ether-hexane, furnishing3a-aldehydoandrostan-17fi-ol and 3,8-aldehydo-androstan-175-01.

Upon treatment by the above procedure of the 170:- substituted compoundsproduced in the preceding example, there were respectively obtained:3u-aldehydo- 17u-methyl-androstan-17 5-01, 3 fi-aldehydo 17ccmethylandrostan-l7fl-ol, 3a aldehydo-l7a-vinyl-androstan-17/3- 01, 35aldehydo 17 a vinyl-androstan-17B-ol, 3m-aldehydo-l7a-ethynyl-androstan17p 01 and 3fl-aldehydol7a-ethynyl-androstan47fl-ol.

Example 111 A solution of 750 mg. of 3a-aldehydo-androstan-l7fi- 01 in50 cc. of tetrahydrofuran was added over a 30 minutes period to astirred suspension of 700 mg. of lithium aluminum hydnide in 50 cc. ofanhydrous tetrahydrofuran. The mixture was refluxed for 2 hours, thencooled, and cautiously treated with 5 cc. of ethyl acetate and 2 cc. ofwater. Solid sodium sulfate was added, the inorganic material filteredoff and thoroughly washed with hot ethyl acetate. The combined organicsolutions upon evaporation yielded a crude material which was purifiedby crystallization from acetone-hexane, thus giving3ahydroxymethyl-androstan-17fl-ol.

All of the above obtained 3-aldehydes were reduced by -method, afiordingthe corresponding products set forth hereafter.

Starting aldehyde Product 3B-aldehydo-androstau-17Eol3a-aldehydo-17a-methyl androstan- 3B hydroxymethyl 17a -methylaudrostan-lm-ol.

3a hydroxymethyl 17a vinyl androstan-Wfi-ol.

3B- aldehydo 17amethyl andro stanstan-UB-ol 3a aldehydo- -17a vinylandro stan-17fl-ol stan-lm-ol 36 hydroxymethyl 17a vinylaudrostan-flfl-ol. 3a aldehyde 17:- ethynyl andro stan-17fl-ol 3ahydroxyrnethyl 17o! ethyn yl androstan-li'fl-ol. 3a aldehydo lia-enthynlandro stan-lIB-ol 3B hydroxymethyl 17a ethynyl 6 Example IV Example V lg. of 3-methoxymethylene-A -androsten-1713-01 was hydrolyzed withperchloric acid in accordance with Example II, to give 3-aldehydo-A-androsten-l7fi-ol.

Upon treatment by the same method of 3-methoxymethylene-l7a-methyl-A-androsten-175-01, 3 methoxymethylene 17a vinyl-A androsten 1718 01, and3- 20 methoxymethylene-l7u-ethynyl-A -androsten17 8-01, there wererespectively obtained: 3 aldehydo-lh-methyl-A androsten l7,Bol, 3aldehyde-17a-vinyl-A -androsten 175-01, and 3 aldehydo-l7a-ethynyl-A-androsten-175-01.

Example VI 750 mg. of 3 aldehydo-d -androsten-17 3-01 were reduced withlithium aluminum hydride following the procedure described in ExampleIII, thus furnishing 3-hydroxymethyl-A -androsten-17/3-01.

When applying this reduction to 3 aldehyde 17amethyl-n -androsten 17 8ol, 3 aldehydo-17a-vinyl-A androsten-l7B-o1, and 3 aldehyde 17aethynyl-A -androsten-17B-ol, there were correspondingly obtained: 3-hydroxymethyl-lh-methyl A androsten-17B-ol, 3-hydroxymethyl-17a-viuy1-A-androsten 17B 01, and 3-hydroxymethyl-17a-ethynyl-A -androsten-175-01.

Example VII 5 g. of A -androsten 17,8-ol-3-one [Butenandt andDannenberg, Ber. 73, 206, (1940)], were treated with 11g. of triphenyl(methoxymethyl) phosphonium chloride, following the technique describedin Example I, thus afiording 3-methoxymethylene-A -androsten-175-01.

Example VIII A solution of the above compound in cc. of pyridine wasadded to a mixture of 5 g. of chromium trioxide in 100 cc. of pyridine.The reaction mixture was kept at room temperature overnight. It was thendiluted with ethyl acetate, filtered through celite and the filtratewashed well with water, dried and evaporated to dryness. Crystallizationfrom acetone-hexane afiorded S-methoxymethylene-A -androsten-17-one.

Example IX A solution of 4 g. of the foregoing steroid in 200 cc. ofthiophene-free benzene was treated with 22 cc. of 4 N methyl magnesiumbromide in ether and the mixture refluxed with the exclusion ofmoisture, for 3 hours. The cooled mixture was cautiously treated withexcess aqueous ammonium chloride solution and the product isolated byethyl acetate extraction. The extract was washed with water, dried overanhydrous sodium sulfate and evaporated to dryness. Recrystallizationfrom methylene chloride-hexane aiforded 3-methoxymethylene-l7amethyl-A-androsten-l7B-ol.

Using exactly the same conditions described above, except that methylmagnesium bromide was substituted by vinyl magnesium bromide and ethynylmagnesium bromide, there were respectively obtained:3-methoxymethylene-l7a-vinyl-A -androsten--01, and 3methoxymet-hylene-l7a-ethynyl-A -androsten-17,8-01.

7 Example X Example XI 750 mg. of 3-aldehydo-A androsten-175-01 werereduced with lithium aluminum hydride in accordance with Example IIIthus furnishing 3-hydroxymethyl-A -androsten-17B-ol.

Following the same method were reduced 3-aldehydol7u-methyl-A -androsten17p o1, 3-a1dehydo 17avinyl-a -androsten-l7;3-o1, and 3 aldehydel7a-ethynyl- A -androsten-17 3-ol, giving correspondinglyS-hydroxymethyl-l7rx-methyl-A -androsten 175 01, 3hydroxymethyl-l7cc-vinyl-A androsten 175 01, and 3 hydr'oxymethyl-17u-ethynyl-A -androsten-175-01.

Example XII A mixture of 500 mg. of 3u-hydroxymethyl-androstan- 1718-01,4 cc. of pyridine and 2 cc. of acetic anhydride was kept at roomtemperature overnight, poured into ice water, the formed precipitate wasfiltered, washed with water and dried. Crystallization fromacetonehexane gave the 17 acetate of 3u-acetoxymethyl-androstan-17fi-ol.

Following the same technique were acetylated 3-hydroxymethyl-A-androsten-17,8-01 and 3-hydroxymethyl- A -androsten-l7B-0l, furnishing3 acetoxymethy1-A -androsten-17B-ol-17-acetate and 3-acetoxymethyl-A-andro sten-17fi-o1-l7-acetate.

By exactly the same procedure except that acetic an hydride Wassubstituted by propiom'c anhydride, caproic anhydride and benzoylchloride, there were obtained res'pectively the dipropionates,di'caproates and dibenzoates of the above diols.

Example XIII 1 g. of Sea-hydroxymethyl-17a methyl-androstan-17fi-ol wastreated with acetic anhydride by the technique described in theforegoing example furnishingBa-acetoxymethyl-17a-methyl-androstan-175-0].

Following the same technique were treated 3a-aldehydoand-rostan-l7fl-ol, 3 aldehydo-A -androstan-l75-01,3-hydroxymethyl-17a-vinyl-A -androsten 17,8 01, and 3-hy'droxymethyl-17a-ethynyl-A -androsten 17,8 01, yieldingcorrespondingly l7-acetate of 3a-aldehydo-androstan- 17 3-01, 17-acetateof 3-aldehydo-A -androsten 175-01, 3- acetoxymethyl-l7a-vinyl-A-androsten 17,8 01, and 3- acetoxymethyl-17a-ethynyl-A-androsten-173-01.

Example XIV A mixture of 1 g. of3fi-hydroxymethyl-17a-methylandrostan-17/3-ol, 1 g. of p-toluenesulfonicacid monohydrate, 50 cc. of acetic acid and 25 cc. of acetic anhydridewas kept for one hour at room temperature. It was then poured into waterand stirred until the excess anhydn'de had hydrolyzed. Isolation of theproduct by methylene chloride extraction and crystallization of theresidue from acetone-ether gaveSfl-acetoxymethyl-lhmethyl-androstan-l7B-ol-17-acetate.

Following the above technique were treated the start- 7 ing compoundslisted below with the acylating agent indicated furnishing the productshereafter set forth.

Starting compound Acylating agent Product 3 hydroxymethyl 17aaceticanhydride- 17-acetate 0i 3-acetoxyethynyl A androstenmethyl-l'h-ethynyl-176-01. N-androsten-HB-ol. 3 hydrox'ymethyl 1764- propionic anhydride17-propionate' of 3- vinyl-N-androsten 17B- propionoxymethylol.l7a-ethynyl-N- androsten-UB-ol.

Do acetic anhydride. i7-acetate of 3-acetoxymethyl-lh-vinyl-N-andtosten-HB-ol.

Do cyclopentyl-pro- 17-cyclopentylpr'opicnic anhydride. pionate ofB-cyclopentyl-propionoxy- 17a-viny1-A andmsten-UB-ol.

3 acetoxymethyl 17a caprolc anhydride.-. 17-caproate of 3-a'eemethylandrostan-HB- toxy-methyl 17ao1. methyl-and'rostan- 3 acetoxymethyl 17apropiontc 17-pr0p1onate 013- vinyl A androsten anhydrideacetoxymethyl-fla- 3 acctoxymethyl 17;:- cyclopentyl- 17-cycl0pentylpropi0nethynyl A" androstenpropionic ate of 3 acetoxyinethyl- 175 01.anhydride. I7a-ethynyLA androsten-UB-ol.

3a-aldehydod7a-methylpropionic lT-proplonate of 3aandrostan-Ufl-ol.anhydride. aldehydo-Ih-methylandrostamlm-ol.

3 aldehyde 17o: vinylcaproic anhydride..- l7-caproate of 3-3-a1d'ehydo-17a-cthy'nylcyclopentyllfi cyclopentylv N-androsten-UB-ol.propionic propionate old-aldeanhydride. hydo-l 7 -ethynyl'-Aandrosteu-Ufi-ol.

Weclaim: l. A compound of the following formula:

wherein R is selected from the group consisting of '-CH0 and CH OR inwhich R is selected from the group consisting of hydrogen and ahydrocarbon carb'oxylic acyl group of less'than 12 carbon atoms; R hasthe same meaning as R and R is selected from the group consisting ofhydrogen,'a1kyl, alkenyl and 'alkynyl groups containing up to eightcarbon atoms.

. 3-aldehydo-A androsten-175-01.

3-aldehydo-17u-vinyl-A -androsten-17B-ol. 3-hydroxymethyl-d-androsten-17,6-01. 3-hydroxymethyl l7oa-vinyl-A -androsten-l lfl-ol.17-acetate of 3-aldehydo-A -androsten-17,8431. l7-acetate of3-acetoxymethyl-l7a-ethynyl-A -androstan-l7fi-ol.

8. A compound of the following formula:

iii

wherein R is selected from the group consisting of C-HO and ---CH OR inwhich R is selected 'from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; R hasthe same meaning as R and R is selected from the group consisting ofhydrogen, alkyl, alkenyl and alkynyl groups containing up to eightcarbon atoms. 7

9 9. 3-aldehydo-A -androstan-1718-01. 10. 3-aldehydo-17a-ethynyl-A-androstan-175-01. 11. A compound of the following formula:

wherein R is selected from the group consisting of CH0 and --CH OR inwhich R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms; R hasthe same meaning as R and R is selected from the group consisting ofhydrogen, alkyl, alkenyl and alkynyl groups containing up to eightcarbon atoms.

12. 3a-aldehydo-androstan-175-01.

13. 3p-aldehydo-androstan-17,9-01.

14. 3a-aldehydo-17a-methyl-androstan-1718-01.

15. 3 5-aldehydo-17 a-methyl-androstan-175-01.

l6. 3a-hydroxymethyl-androstan 17 8-01.

17. 3p-hydroxymethyl-androstan-17,8-01.

18. 3a-acetoxymethyl-androstan-17p-ol-17-acetate.

19. 3a-acetoxymethyl-l7a-methyl-androstan-175-01.

20. A process for the production of 3-hydroxymethyl androstanederivatives which comprises treating the corresponding 3-ketone withtriphenyl (methoxymethyl) phosphonium chloride in the presence of acompound selected from the group consisting of an alkyl lithium and anaryl lithium to give the corresponding 3-methoxymethylene compound,hydrolyzing the latter compound and thereafter reducing the thus formed3-aldehydo derivative with a double metal hydride.

21. The process of claim 20 wherein the aryl lithium compound is phenyllithium and the double metal hydride is lithium aluminum hydride.

No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA: